Management of malignant glioma

STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARYA 60-year-old engineer presented to the emergency department at a district general hospital describing a vacant episode (he was aware of his surroundings but unable to respond to or to interact with people around him) accompanied by dysphasia and disorientation lasting around three hours. After this episode he noticed a slight tremor, weakness and pins and needles (paraesthesia) in his right hand.
He had experienced a similar episode a month earlier, lasting for 40 minutes, and this had been diagnosed as a transient ischaemic attack (TIA) and led to a prescription for aspirin and dipyridamole. Past medical history included hypertension and benign prostatic hyperplasia. He was a non-smoker, who rarely consumed alcohol and he had no known allergies to drugs or substances.


Regular medication on presentation was as follows:

  • Aspirin 75mg od
  • Dipyridamole MR 200mg bd
  • Finasteride 5mg od
  • Doxazosin 2mg od

Diagnosis

Computed tomography revealed a heterogeneous rounded lesion of approximately 3.7cm in the left posterior temporal region with surrounding oedema. Magnetic resonance imaging with contrast revealed patchy enhancement and a provisional diagnosis of an aggressive solitary tumour, likely to be a high-grade glioma (see Panel), was made.

What are malignant gliomas?

Malignant gliomas are the most common type of primary brain tumour, with approximately 1,860 new diagnoses in England and Wales each year.1 Derived from the glial cells of the central nervous system, they are graded using the World Health Organization classification scale of I to IV depending on their histology and likely rate of growth. Grades III and IV gliomas are termed “high-grade” gliomas.1,2

Definitive diagnosis of a high-grade glioma requires tumour tissue samples taken during resection or biopsy. However, provisional diagnosis can be made using clinical examination and either computed tomography or magnetic resonance imaging.1

Standard treatment involves surgical resection, followed by adjuvant radiotherapy (and sometimes chemotherapy) where possible.

The prognosis for patients with high-grade gliomas remains poor with standard treatment (median survival is less than two years), owing to the aggressive, infiltrative nature of these tumours as well as their tendency to recur post-resection (usually within 2cm of resection site).3–5

In recent years, two products have been introduced into practice allowing doctors to overcome some of the barriers to the efficacy of standard treatment in selected patients:

  • 5-Aminolevulinic acid powder (Gliolan)
  • Carmustine intracerebral implants (Gliadel)

Management

After discussion at the central nervous system multidisciplinary team (CNS MDT) meeting a decision was made to proceed with fluorescence-guided tumour resection, with or without insertion of chemotherapy wafers, depending on intraoperative histology results. While awaiting surgery, planned for the following week, the patient was started on dexamethasone 4mg bd (to ameliorate the presenting symptoms caused by tumour-associated oedema6) and lansoprazole 30mg od for gastroprotection.

His aspirin and dipyridamole were stopped indefinitely in view of the likelihood that the previous diagnosis of TIA was incorrect.
On the day of surgery, the patient was given 2g of 5-aminolevulinic acid four hours before induction of anaesthesia.

5-Aminolevulinic acid

5-Aminolevulinic acid (5-ALA/Gliolan) has been granted orphan drug status for the intraoperative photodynamic diagnosis of residual glioma. It is a prodrug that is metabolised to fluorescent porphyrins, particularly protoporphyrin IX. Protoporphyrin IX selectively accumulates in high-grade glioma cells and fluoresces on excitation with blue light at a wavelength of between 400 and 410nm, allowing the neurosurgeon to differentiate between the tumour and normal tissue.7 This facilitates maximal tumour resection, which has been shown to have a beneficial effect on survival as well as the potential to improve the efficacy of adjuvant treatment.8,9

5-ALA is given orally at a dose of 20mg/kg, between two and four hours before induction of anaesthesia.7

In one trial involving 322 patients, randomised to receive either fluorescence-guided surgery with 5-ALA or conventional microsurgery (with white light), patients in the 5-ALA group were 29 per cent more likely to be without residual, contrast-enhancing tumour on early MRI (within 72 hours). Patients in the 5-ALA group were also statistically more likely to be progression-free at six months (41.0 per cent versus 21.1 per cent). However, overall survival did not differ between groups.10

Histology from the samples taken intra-operatively confirmed a grade IV tumour (glioblastoma multiforme) and five carmustine wafers were implanted into the resection cavity (see below).

Carmustine implant wafers

Carmustine wafers (Gliadel) are indicated for the treatment of patients with newly diagnosed high-grade glioma as an adjunct to surgery and radiation and of those with recurrent glioblastoma multiforme for whom surgical resection is indicated. (Note that the National Institute for Health and Clinical Excellence has only approved its use for newly diagnosed patients. Use for patients with recurrent glioblastoma multiforme was rejected by NICE on the basis that the manufacturer did not provide an evidence submission for use in this group).1,11,12

The implant wafers consist of a biodegradable copolymer disc impregnated with the alkylating agent carmustine. Up to eight wafers, each about the size of a five pence coin, can be implanted in the surgical resection cavity, if 90 per cent or more of the tumour has been resected.1 The number of wafers implanted depends on the shape and size of the resection cavity.

On exposure to the aqueous environment of the cavity, anhydride bonds in the copolymer are hydrolysed. Carmustine is released from the wafer and can diffuse into the surrounding tissue.11

The largest trial to date has been a multinational, placebo-controlled trial involving 240 patients with primary malignant glioma, randomised to receive either carmustine or placebo wafers at the time of primary surgical resection.13 An intention-to-treat analysis of the primary endpoint — overall survival — revealed a statistically significant increase in survival time (13.9 versus 11.6 months) and a 29 per cent reduction in the risk of death in patients treated with carmustine. When the results were analysed for a subgroup of patients with glioblastoma multiforme specifically, carmustine also conferred survival benefit, which was statistically significant when results were corrected for prognostic factors. Adverse events were similar in both groups. Results from this trial were combined with those of a smaller trial, involving 32 patients, in a Cochrane review of chemotherapy wafers for high-grade glioma.2 This review concluded that carmustine wafers do confer a survival benefit in the treatment of primary high-grade gliomas. (Although it is beyond the scope of this article, it should be noted that the review concluded no survival benefit when used in the treatment of recurrent disease.)

Role of the pharmacist

Pharmacists can lead or support the development of a robust policy and procedure to enable multidisciplinary staff to manage the application of new therapies, such as Gliolan and Gliadel, in practice. They can also ensure that effective procurement systems are in place such that stock is available when it is requested. In addition, they should keep accurate records of administration of each treatment (in order to facilitate clinical audit of adherence to protocol/policy and for assessment of local outcomes) and report regularly on monthly divisional expenditure for both treatments. It is worth noting treatment costs at this point which, at the time of writing were in excess of £650 per carmustine wafer and in excess of £900 per 1,500mg vial of 5-ALA.

Patients with glioma are a priority for pharmacists working within the specialties of neuroscience and oncology. Those who are first on the operating list might need to be given 5-ALA in the early hours of the morning (ie, out of hours). This requires prescriptions to be processed in advance, requiring effective communication between the treating team, the pharmacist and the ward staff.

The pharmacist needs to ensure hepatotoxic medicines are withheld for 24 hours post dose, owing to associated risk of hepatobiliary disorders (a very common procedure-related side effect).7 He or she will also need to ensure that photosensitising medicines are withheld for up to two weeks where possible and, in addition, that the patient is aware of the need to avoid exposure of skin and eyes to bright light for 24 hours post-dose and to avoid exposure of the skin to strong sunlight for up to two weeks owing to an associated risk of photosensitivity and photodermatosis.
For the use of carmustine implant wafers, pharmacists should ensure that facilities are available for appropriate storage until immediately before use. Carmustine wafers should be stored at or below –20C (ie, in a freezer). Once wafers have been removed from the freezer they cannot be refrozen unless they are unopened and have been exposed to temperatures of up to 22C for no more than six hours, at which point they will be given a shortened expiry of 30 days. There are, therefore, significant cost implications if wafers are removed from storage inappropriately.

The pharmacist needs to ensure that the carmustine wafers are available for collection by a member of neurotheatre staff on receipt of intraoperative histology results confirming high-grade glioma. He or she will then need to ensure that an alert is added to the patient’s (electronic) medical record, detailing the date of implantation of the carmustine wafers in view of local policy to consider any wound leak up to six weeks post-operation as potentially containing cytotoxic material. It is imperative that any items contaminated by a leaking wound are handled in accordance with local guidance for the management of cytotoxic waste.

What happened next

One day after surgery, the patient was well but still expressively dysphasic so his dexamethasone was increased to 8mg bd and a referral to the speech and language therapist was made. Three days after the operation he was well enough to be discharged, with an appointment to be seen in clinic after two weeks for follow-up and future treatment planning.

This case highlights the pivotal role of the pharmacist in the management of patients with high-grade glioma treated with new therapies. From the procurement and storage of the drugs, and the education of the nursing and medical staff around their safe handling and administration, to producing clear post-operative documentation to facilitate future management and accurate financial recording and reporting, it is crucial that pharmacy is involved in the patient pathway from start to finish.

Although beyond the scope of this article, the role of the pharmacist in the management of patients with a glioma — a diagnosis is devastating to both patients and to their carers — extends far beyond the management of new therapies. Despite allowing doctors to overcome some of the barriers to efficacy associated with standard treatment, as discussed above, these therapies do not necessarily offer more than a modest benefit.

The typical prognosis for patients with glioma requires that the priority of care is quality of life, such that there is also significant scope for contribution to management of associated symptoms, such as pain, nausea, vomiting and seizures and ultimately of palliation.

Case comment: Steve Williamson, consultant pharmacist in cancer services

This case report is fairly typical of a highly specialised treatment in a rare cancer. It shows how pharmacists can develop skills to support specialist clinical teams, such as neuro-oncology. The technology behind drug impregnated wafers used as an adjunct to resection of malignant gliomas represents an interesting novel approach to cancer treatment. It is also positive to see older drugs, such as carmustine, getting a new lease of life via these systems.
Unfortunately, as for most new cancer treatments, the clinical benefits are small with only modest improvement (a few weeks) in progression-free and overall survival for the average patient. It is also difficult to truly quantify the benefit because it is unclear how much of the outcome depends on the skill of the surgeon. But the key term here is “average patient”. In many cancer diagnoses patients face a potentially bleak outcome and any treatment that offers hope becomes desirable, because every patient has the potential to do better than average and derive greater benefit from these treatments.

Key points

  • 5-Aminolevulinic acid oral powder and carmustine intracerebral implants are improving the efficacy of surgery in some patients with brain tumours.
  • Pharmacists can lead or support the development of robust policy and procedure to enable multidisciplinary staff to manage the application of new therapies.
About the author

Laura Marsland MPharm, ClinDip, is a locum pharmacist and was previously lead pharmacist for neuroscience, stroke and rehabilitation at Cambridge University Hospitals NHS Foundation Trust

Citation: The Salvadore DOI: 10.1211/PJ.2013.11116807

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